Expression of four growth factors, transforming growth factor alpha (TGF-alpha), acidic fibroblast growth factor (aFGF), hepatocyte growth factor (HGF), and stem cell factor or kit ligand (KL), are associated with proliferation and differentiation of oval cells in the liver. The highest expression of TGF-alpha, aFGF and KL coincides with the major expansion and differentiation of the oval cell compartment, whereas the HGF expression precedes the major oval cell proliferation. Similarly, HGF expression precedes that of TGF-alpha and aFGF after partial hepatectomy. In contrast, the time course of TGF-alpha, aFGF and HGF expression in postnatal liver is similar. Since the liver is a hemopoietic organ in fetal life and can provide a site of extra-bone marrow hemopoiesis in the adult animal, the expression of KL and c-kit during oval cell growth and differentiation may suggest similarities in the microenvironments that promote differentiation in both bone marrow and in the liver. Combination of in situ hybridization and immunocyto- chemistry demonstrated that the presence of HGF transcripts was selectively localized in Ito cells, whereas its receptor, encoded by the c-met proto-oncogene, is presented in oval cells. Therefore, HGF may initiate the proliferation of the primitive hepatic stem cells, of which the oval cell is a progeny, via the paracrine mechanism. Since the highest expression of KL, TGF-alpha and aFGF occurs during both growth and differentiation of the oval cells, it seems likely that these growth factors may play an important role in the lineage commitment of the oval cell compartment.